Basic derivatives of substituted cinnamic acids and methods of preparing same



Patented May 4, 1954 UNITED STATES PATENT OFFICE BASIC DERIVATIVES OF SUBSTITUTED CINNAMIC ACIDS AND METHODS OF PREPARING SAME William A. Lott, Maplewood, N. J., assignor to Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Application August 30, 1951, Serial No. 244,473

Claims. 1 This invention relates to, and has for its object the provision of, compounds of the class consisting of: (A), bases of the general formula (Monocyclic aryl)-Cl=(J-C OX-(divalent aliphatic radicaD-Y R 11 wherein one B. represents a member of the class consisting of aryloxy and arylmercapto groups, and the other R, represents hydrogen, Y represents the radical of an amine, and X represents a member of the group consisting of O, NH, and N(alkyl);(B), acid-addition salts thereof; (C), quaternary ammonium salts thereof; and (D), methods of preparing (A), (B) and (C). (The monocyclic aryl group may be unsubstituted or may contain substituents such as alkyl, alkoxy, hydroxy and halo groups.) These compounds are promising therapeutic agents, especially antispasmodics.

Among the preferred compounds are: bases having the following general formula wherein one B. represents aryloxy and the other R. represents hydrogen, X has the meaning given hereinbefore, and Z represents a member of the class consisting of /(lower alkyl) N (lower alkyl) l-piperidyl, l-pyrolidyl, and 4-morpholinyl groups; the acid-addition salts of said :bases; and, the quaternary ammonium salts (with alkyl halides) of said bases.

The basic esters are prepared by a method which essentially comprises interacting an acid (I) of the general formula with a basic aliphatic halide (II) of the general formula (halogen)-(divalent aliphatic radica1)Y in an organic solvent for the reactants (especially isopropanol) Thus the following reactants may be used in the practice of this invention:

a-Phenoxycinnamic acid ,B-Phenoxycinnamic acid B-p-Cresoxycinnamic acid fi-a-Naphthoxycinnamic acid a-Phenoxy-p-hydroxycinnamic acid (U. S. Pat.

a-Phenylmercapto p hydroxycinnamic acid (U. S. Pat. 2,503,296)

3- (Z-methoxyphenoxy) -cinnamic acid al-bromo-phenoxy) -cinnamic acid fi-(2,4-dimethylphenoxy) -cinnamic acid 5- (2,4-dimethylphenylmercapto) -cinnamic acid p-Naphthylmercapto-cinnamic acid fi-PhenoXy-p-methoxycinnamic acid p-Phenoxy-p-methylcinnamic acid p-Phenoxy-p-chlorocinnamie acid B-Diethylaminoethyl chloride -Diethylaminopropyl chloride 7- l-piperidyl) -propyl chloride 18-(1-pyrrolidyl) -ethyl chloride fl-( i-morpholinyl) -ethyl chloride -Diethylamino-cfi-dimethylpropyl chloride 8- l-piperidyl) -ethyl chloride B-Diethylaminoisopropyl chloride fi-Dimethylaminoisopropyl chloride fl-Chloroz-diethylaminobutane The basic amides are prepared by a method which essentially comprises interacting an acyl' halide, derived from acids I, with an aliphatic diamine (IV) containing at least one free amino hydrogen, in an organic solvent for the reactants. The utilizable diamines IV include inter alia:

N,N-diethylethylenediamine 1- (p-aminoethyl) -piperidine 1-amino-5-diethylaminopentane 1-amino -4-diethy1aminobutane (p-Dimethylaminoethyl) -amino] -ethane N,N-dimethylethylenediamine N ,N-dipropylethylenediamine In the above methods the acid-addition salts (e. g., the hydrochlorides, if the halogen reactant These B-substituted cinnamic acids may be obtained by the method described in .T. C. S. 77, 984 (1900),

is chlorine) rather than the free bases are ordinarily obtained. If desired, these acid-addition salts may be converted to the free bases in the conventional manner, i. e., by neutralization with alkali; and the free bases may be converted to other acid-addition salts by reacting the base with the desired acid in a suitable solvent. The utilizable acids comprise, inter alia: hydrobroniic, boric, nitric, lactic, tartaric, citric, succinic, phosphoric, sulfuric, maleic, fumaric and (especially) hydrochloric.

By the addition of alkyl halides, alkylene halides, aryl sulfonic acid esters, dialkyl sulfates, aralkyl halides, aryl halides, or the like, there are obtained in the usual manner quaternary salts of the basic esters and amides (A) described hereinbefore.

The following examples are illustrative of the invention:

EXAMPLE 1 N (p-diethylamz'noethyi) -e-phenorycinnamamide hydrobromide A solution of 27 g. l l,N-diethylethylenediamine in 200 ml. benzene is added dropwise with cooling (10 C.) to a solution of 60 g. oz-ZJhSIlOXY- cinnamoyl chloride in 360 ml. benzene. The mixture is refluxed for two hours, at which time about 75% of the benzene is distilled and the residue is cooled and diluted with 500 in]. ether.

The precipitated gum is then dissolved in ace ml. water, and extracted with 200 ml. ether. The aqueous solution is alkalinized with potassium carbonate extracted with 250 ml. ether and the extracts are dried and acidified with dry hydrogen bromide until faintly acid to Congo red paper. The product, recrystallized from 1'20 ml. ethanol, yields about 26 g. of the hydrobromide acid-addition salt, melting at about 124-125" (3.

EXAMPLE 2 [3- (Dz'ethylammoethyl) -a-pherloxyemnamate hydrochloride A solution of 12 g. a-phenoxycinnamic acid and 6.78 g. fi-diethylaminoethyl chloride in 100 ml. isopropanol is refluxed for two hours, and the isopropanol removed under reduced pressure. The residue when recrystallized three times from 125 m1. ethanol yields about 11.4 g. of the acid-addition salt melting at about l721'73 C.

EXAIAPLE 3 N 5-Dlmethylamin0ethyl) -cpheno:nycih namamide hydrochloride A solution of 8.5 g. N,l l-dimethylethylenediamine in 100 ml. benzene is added dropwise with cooling C.) to a solution or" g. a-phenoxycinnamoyl chloride in 190 ml. benzene. After the mixture has been allowed to stand overnight, the product is filtered and recrystallized from 210 ml. of an alcohol-ether solution to give about 22 g. of the acid-addition salt melting at about 158- 159 C.

EXAMPLE 4 N p-Dipropylaminoethyl) -u.-pheno:cycinnamamide hydrochloride A solution of 13.95 N,N-dipropylethylenediamine in 100 ml. benzene is added to a solution of 25 g. a-phenoxycinnamoyl chloride with cooling at 10 C. After the addition, the mixture is refluxed for three hours, cooled and diluted with ether. The product is filtered and recrystallized from 160 ml. methyl ethyl ketone to give 13 g. of

4 the acid-addition salt melting at about 134- 135 C.

EXAMPLE 5 ,9- (Diethylaminoethyl) -;8-phenoxyclnnamate hydrochloride A solution of 12 g. B-phenoxycinnamlc acid [J. Chem. Soc. 7'7, 985 (1900)] and 6.7 g. fl-diethylarninoethyl chloride in 100 ml. of isopropanol is refluxed for seven hours; and the isopropanol is distilled off and the residue dissolved in water. The solution is alkalinized with potassium carbonate and extracted with 200 ml. ether. The ether solution is then dried over magnesium sulfate and removed by distillation. The residue is fractionated to give about 9 g. of product boiling at about 189 C./0.5 mm. This material is dissolved in 200 ml. ether and ethereal hydrogen chloride is added until acid to Congo red paper. The precipitate is filtered and recrystallized twice from 210 ml. of an alcohol-ether solution to give about 7 g. of the acid-addition salt melting at about 123-124" 0.

EXAMPLE 6 Using a molar equivalent of u-phenylmercaptop-hydroxycinnamoyl chloride, prepared by reacting the corresponding acid (of. U. S. Patent 2,503,296) with thionyl chloride, in place of e-phenonycinnamoyl chloride in Example 3, the corresponding N (,3 dimethylaminoethyl) a. phenylmercapto-p-hydroxycinnamamide hydrochloride is prepared.

In place of benzene used in the foregoing examples, one may use other organic solvents for the reactants, inter alia, ether and toluene.

The acid-addition salts prepared in Examples 1 through 6, converted to free bases, in the conventional manner, are used to prepare the following quaternary ammonium salts. (If an acidbinding agent is present, the free base is obtained immediately, and the quaternary compounds can be prepared from this by a more direct route.)

EXAMPLE 'l [5- (a-Phenoxycinnamoyloxy) ethyl] -diethylmethylammonium bromide EXAMPLE 8 [p (a Phenoazycirmamido) ethyl] trzethylammom'um bromide A solution of 15 g. N-(p-diethylaminoethyD- a-phenoxy-cinnarnamide [prepared from the acid-addition salt (cf. Example 1) in the manner described in the preceding example] in 20 ml. of benzyl alcohol, and 10 g. ethyl bromide in 50 ml. benzyl alcohol is heated at 50 C. for two days, cooled and diluted with 200 ml. ether. The precipitate is filtered and recrystallized from ml. of an ethanol-ether solution to give about 8 g. of material melting at about 109-'111 C.

EXAMPLE 9 [;9- (a-Phenorcycinnamido) ethyl] diethylmethylammonium bromide EXAMPLE 10 [B (u Phenomycinnamido) ethyl] dz'propylmethylammonium bromide A solution of 8 g. N-(c-dipropylaminoethyl) -aphenoxy-cinnamamide, prepared from the acidaddition salt (cf. Example 4) in ml. of methanol, and 6.1 g. of methyl bromide in 35 ml. of methanol is allowed to stand at room temperature for two days. Upon diluting with 200 ml. ether a precipitate forms which is filtered and recrystallized from '75 ml. of a butanol-ether solution to give about 6 g. of material melting at about 177-178" C.

EXAMPLE 11 [p (a Phenoxycinnamidmethyl] dimethyb ethylammom'um iodide A solution of 10 g. of N-(B-dimethylaminoethyl) -u-phenoxy-cinnamamide, prepared from the acid-addition salt (of. Example 3) in 20 ml. of acetone, and 15.1 g. of ethyl iodide in 100 ml. of acetone is allowed to stand in a pressure bottle at room temperature for two days. The precipitate is triturated with 100 ml. ether, filtered and recrystallized from ml. of an ethanolether solution to give about 2 g. of material melting at about 181'182 C.

EXAMPLE 12 [e (a Phenoxycinnamz'dmethyl] diethylmethylammom'um iodide A solution of 20 g. of N-(fl-diethylaminoethyl) u-phenoxycinnamamide, prepared from the acidaddition salt (of. Example 1) in 20 ml. of acetone, and 14 g. of methyl iodide in 100 ml. of acetone and 50 ml. of benzyl alcohol is heated at 50 C. for two days. The solution is cooled and diluted with 350 ml. ether. The solid is filtered and recrystallized from 320 ml. of an ethanol ether solution to give 17.5 g. of material melting at about 144-145 0.

EXAMPLE 13 Using a molar equivalent of u-phenylmercaptop-hydroxycinnamic acid, in place of a-phenoxycinnamic acid, in Example 2, the corresponding ,8- (diethylaminoethyl) x-phenylmercapto-p hydroxycinnamate hydrochloride is prepared; and a quaternary ammonium salt thereof is prepared as described in Example 7.

EXAMPLE 14 Using a molar equivalent of p-(diethylaminoethyl) -i '-phen0xycinnamate, prepared from the acid-addition salt (of. Example 5), in place of fl-(diethylaminoethyl) -u-phenoxycinnamate, in Example 7, [B- (B-phenoxycinnamoyloxy) ethyl] diethylmethylammonium bromide is obtained.

The invention may be variously otherwise embodied within the scope of the appended claims.

I claim:

1. Compounds of the group consisting of the free base, its acid-addition salts and its lower alkyl halide quaternary salts, the free base having the formula wherein one R represents hydrogen, the other R being a member of the class consisting of phenoxyand phenylmercapto-; and X is a member of the class consisting of O and NH.

2. The process which comprises reacting (A) a compound of the formula (lower alkyl) E(lower alkylene)N (lower alkyl) wherein E is a member of the class consisting of hydroxy, halo, and NH2, with (B) a compound of the formula wherein one B. represents hydrogen, the other R being a member of the class consisting of phenoxyand phenylmercapto-; and D is hydroxy when E is halo and halo when E is a member of the class consisting of hydroxy and NH2; and recovering the reaction product.

3. Compounds of the general formula lower alkyl C sHr-CH=CCOO(10WBI a1kylene)-N O- CaHs lower alkyl 4. Compounds of the general formula 0 O 0115 lower alkyl 5. Acid-addition salts of the compounds of claim 3.

6. Acid-addition salts of the compounds of claim 4.

7. Lower alkyl halide quaternary salts of the compounds of claim 3.

8. Lower alkyl halide quaternary salts of the compounds of claim 4.

9. The compound 8(u-phen0xycinnamoyloxy) ethyl] -diethylmethy1ammonium bromide.

10. The compound [B-(a-phenoxycinnamidmethyl]-diethylmethylammonium bromide.

11. The compound [fl-(a-phenoxycinnamido)- ethyl] -dipropylmethylammonium bromide.

12. The compound [fi-(a-phenoxycinnamido) ethyl] diethylmethylammonium bromide.

'13. The compound [/i-(a-phenoxycinnamido)- ethyl] -triethylammonium bromide.

14. The process of claim 2, wherein the reaction product obtained is reacted with an acid to form an acid-addition salt.

15. The process of claim 2, wherein the reaction product obtained is reacted with an ester of an inorganic acid to form a quaternary ammonium salt.

No references cited. 

1. COMPOUNDS OF THE GROUP CONSISTING OF THE FREE BASE, ITS ACID- ADDITION SALTS AND ITS LOWER ALKYL HALIDE QUATERNARY SALTS, THE FREE BASE HAVING THE FORMULA 